Urinary incontinence is the involuntary discharge of urine. This occurs in an uncontrolled manner when the pressure within the urinary bladder exceeds the pressure needed to close the ureter. Causes can be on the one hand an increased internal pressure in the bladder (e.g. due to detrusor instability) with the consequence of urgency incontinence and on the other hand a reduced sphincter pressure (e.g. following giving birth or surgical interventions) with the consequence of stress incontinence. The detrusor is the coarsely bundled multilayered bladder wall musculature, contraction of which leads to discharge of urine, and the sphincter is the closing muscle of the urethra. Mixed forms of these types of incontinence and so-called overflow incontinence (e.g. in cases of benign prostate hyperplasia) or reflex incontinence (e.g. following damage to the spinal cord) occur. Further details in this respect are to be found in Chutka, D. S. and Takahashi, P. Y., 1998, drugs 560: 587–595.
The urge to urinate is the state, aimed at discharge of urine (miction), of increased bladder muscle tension as the bladder capacity is approached (or exceeded). This tensioning acts here as a stimulus to miction. An increased urge to urinate is understood here as meaning in particular the occurrence of a premature or increased and sometimes even painful urge to urinate up to so-called strangury. This consequently leads to significantly more frequent miction. Causes can be, inter alia, inflammations of the urinary bladder and neurogenic bladder disorders, and bladder tuberculosis. However, all causes have not yet been clarified.
An increased urge to urinate and urinary incontinence are extremely unpleasant and there is a clear need among persons afflicted by these conditions to achieve an improvement which is as long-term as possible.
An increased urge to urinate and in particular urinary incontinence are conventionally treated with medicaments using substances which are involved in the reflexes of the lower urinary tract (Wein, A. J., 1998, Urology 51 (suppl. 21): 43–47). These are usually medicaments which have an inhibiting action on the detrusor muscle, which is responsible for the internal pressure in the bladder. These medicaments are e.g. parasympatholytics, such as oxybutynin, propiverine or tolterodine; tricyclic antidepressants, such as imipramine; or muscle relaxants, such as flavoxate. Other medicaments, which in particular increase the resistance of the urethra or of the neck of the bladder, show affinities for α-adrenoreceptors, such as ephedrine, for β-adrenoreceptors, such as clenbutarol, or are hormones, such as oestradiol.
Certain diarylmethylpiperazines and -piperidines are also described for this indication in WO 93/15062. For tramadol also a positive effect on bladder function has been demonstrated in a rat model of rhythmic bladder contractions (Nippon-Shinyaku, WO 98/46216). The literature furthermore contains studies on characterization of the opioid side effect of urine retention, which give some indications of the influence on bladder functions by weak opioids, such as diphenoxylate (Fowler et al., 1987 J. Urol 138:735–738) and meperidine (Doyle and Briscoe, 1976 Br J Urol 48:329–335), by mixed opioid agonists/antagonists, such as buprenorphine (Malinovsky et al., 1998 Anesth Analg 87:456–461; Drenger and Magora, 1989 Anesth Analg 69:348–353), pentazocine (Shimizu et al. (2000) Br. J. Pharmacol. 131 (3):610–616) and nalbuphine (Malinovsky et al., 1998, loc. cit.), and by potent opioids, such as morphine (Malinovsky et al., 1998 loc. cit.; Kontani and Kawabata, (1988); Jpn J Pharmacol. Sep;48(1):31) and fentanyl (Malinovsky et al., 1998 loc. cit.). However, these studies were usually conducted in analgesically active concentrations.
In the case of the indications in question here, however, it should be remembered that it is in general a matter of very long-term uses of medicaments and, in contrast to many situations where analgesics are employed, those affected are faced with a situation which is very unpleasant but not intolerable. It is therefore to be ensured here—even more so than with analgesics—that side effects are avoided if the person affected does not want to exchange one evil for another. Also, analgesic actions are also largely undesirable during permanent treatment of urinary incontinence.